Technical Brief 2010 Volume 9
Cleanroom Operations
Background
Cleanrooms are defined as a
room or suite of rooms, in which
the concentration of airborne par-
ticles is maintained within estab-
lished parameters and where other
factors are controlled to within
specified limits. These rooms are
designed to provide control of en-
vironmental factors including:
• Viable and non-viable airborne
particles
• Air flow patterns
• Temperature and humidity
• Air pressure differential
• Containment of hazardous
aerosols
Applications include the manu-
facture of sterile and non-sterile
pharmaceutical and biotech prod-
ucts, medical devices, and im-
plants. These rooms are also used
to manufacture sensitive electron-
ics. However, the requirements for
these latter applications are not
the objective of this article. GMP
requirements from the different
Boards of Health, including the
US Food and Drug Administration
(FDA), for sterile pharmaceutical,
biotech, medical devices and im-
plants require the manufacture of
these products are performed in
clean environments that meet the
requirements of standards such as
ISO EN146441.
Compliance Requirements:
• FDA Guideline Sterile Drug
Products Produced by Aseptic
Processing2
• European Union (EU) GMP
Annex 13 Manufacture of Sterile
Medicinal Products
Other Helpful Documents:
• ISO EN14644-1, -2
• International Society for Phar-
maceutical Engineering (ISPE4)
Air Handling Requirements
Room air should be supplied
by an external air conditioning
system, preferably dedicated to
the facility. Partial recirculation
of room air is appropriate and this
allows for optimal energy utiliza-
tion. Sufficient fresh air should be
supplied in accordance with ven-
tilation codes, to balance exhaust
air and to maintain specified pres-
sures. Unless, otherwise speci-
fied, typical temperature range
for this kind of room is within the
range of 16 to 19 °C and relative
humidity of approximately 50% is
maintained. The type of equip-
ment and number of people in
the room may dictate where in the
range you need to be to assure that
during production the operations
area is maintained at the right
temperature and humidity levels.
Only HEPA filtered air should
enter the cleanroom and the gown-
ing areas. These modules are
available in fan assisted with fan
speed control and should oper-
ate at a velocity of 90 ± 10 fpm
or 0.45 ± 0.05 m/s. The location
of the HEPA filters and air return
grilles should create air movement
from the designated ‘clean zone’ to
the ‘less clean’ zones. Return air
grilles should be at a lower level to
aid in laminar flow requirements.
Air supply to the cleanroom
should provide a room air change
rate of >20 per hour. Air clean-
liness will be enhanced by higher
air change rates. When the doors
are opened the supply air volume
should maintain an outward flow
of air.
Table 1
People Activity
Motionless (Standing or Seated)
Walking about 2 mph
Horseplay
Old Fed Std 209E ISO EN14644 EU GMP Annex 1 particles per m3 equal to or
100 ISO 5
1,000 ISO 6
10,000 ISO 7
100,000 ISO 8
*Requirements for particle counts during operation are different from class A, 35,200 particles at 0.5 µ
©2010 Particle Sciences, Inc. All rights reserved.
Sources of Contamination more restricted the air flow, the
In order to control contamination, more turbulence and this can
operators and those in charge of a cause undesireable particle
cleanroom need to be cognizant of movement.
sources of contamination. These • Filtration – In addition to the
include: HEPA filters commonly used in
1. Facilities: walls, floors and cleanrooms, there are a number
ceilings; paint and coatings; spills of other filtration mechanisms
used to remove particles from
and leaks
gases and liquids used in the
2. People: skin flakes and oil; manufacture of pharmaceutical
cosmetics and perfume; spittle; products. These filters are
clothing debris (lint, fibers, etc.); essential for providing effective
hair contamination control.
3. Tool-generated: friction and • Cleanroom Garments – The
wear particles; lubricants and requirements for cleanroom
emissions; vibrations; brooms, garments will vary from location
mops, and dusters
to location. It is important
4. Fluids: particulates floating in air; to know the local cleanroom
bacteria, organics, and moisture; garment requirements. Gloves,
floor finishes or coatings; face masks and head covers
cleaning chemicals; plasticizers are standard in nearly every
(outgasses); water cleanroom environment as well
5. Product-generated: glass flakes; as coveralls.
cleanroom debris; aluminum • Personnel - There are both
particles from vial caps physical and psychological
Key Elements of Contamination Control concerns when humans
are present in cleanrooms.
• Cleanroom Architecture – Physical behavior like fast
Cleanrooms are designed to motion and horseplay can
achieve and maintain an airflow increase contamination.
in which essentially the entire Psychological concerns like
body of air within a confined comfort, claustrophobia, strong
area moves with uniform velocity odors, and workplace attitude
along parallel flow lines. This air are important. Below are
flow is called laminar flow. The several ways people produce
contamination:
◊ Behavior-- Rate of move-
Particles/Minute (≥0.3 μ) ment, sneezing and coughing
100,000 ◊ Attitude-- Work habits and
communication between
5,000,000
workers
100,000,000 People are a major source of
contamination in the cleanroom
Table 2
Maximum permitted
Maximum Microbiological
greater than tabulated size Active Air Action Levels
At rest In operation (cfu/m3)
0.5 µ 0.5 µ
Class A & B* 3,520 3,520 1
--- 7
35,200 ---
Class C 352,000 3,520,000 10
Class D 3,520,000 Not defined 100
(Table 1). Notice the number of
particles produced per minute
during these activities.
Cleanroom Classifications
Cleanroom Classifications as
specified by different standards
are shown in Table 2. Non-sterile
products are typically produced in
an ISO 8 or EU Class D environ-
ment. Sterile products are required
to be filled and stoppered in an
ISO 5 or EU Class A environment.
Cleanroom Cleaning
As an example, here are some
recommended procedures for
cleaning a Class C or ISO 7 Area
cleanroom. These procedures are
simply guidelines, not standards
or rules. It is important to review
all cleaning procedures to be used
in a cleanroom with responsible
management. A detailed cleaning
schedule should be prepared for
every cleanroom.
Procedure
Good housekeeping and main-
tenance of the cleanroom and the
associated restricted areas are es-
sential to assure quality. Cleaning
of an active cleanroom should be
performed daily. However, if the
room is not used daily, a different
schedule may be implemented,
but it should be cleaned after
every use. Improper cleaning of
the cleanroom can lead to con-
tamination and compromise prod-
uct quality. Proper selection of
equipment, cleaning agents and
cleaning materials is important
for proper cleaning. Only prod-
ucts that have proven cleanroom
performance records should be
considered for use. These prod-
ucts should be listed in appropri-
ate policies or procedures and all
vendors should be informed about
the strict policies of how prod-
ucts are qualified. All procedures
should be strictly enforced. Below
are some examples of how to or-
ganize cleanroom cleaning. These
are guidelines for preparing work
procedures and schedules. Local
requirements must be included in
any cleaning program.
• Cleanroom mops
• Cleanroom vacuum cleaner
(if allowed)
• Cleanroom wipers
• Cleanroom mop bucket and
wringer
Cleaning Tasks – frequency may
vary depending upon local require-
ments
• Cleaning of all work surfaces in
the controlled environment
• Vacuuming (if allowed) of the
floors and work surfaces
• Emptying of appropriate trash • Gloves should not be allowed
and waste receptacles
• Cleaning of the doors, door
frames and lockers in the pre-
staging area and gowning areas • Only approved gloves, pliers,
using the approved cleaning
solution
• Mop gowning area and cleanroom • All tools, containers and fixtures
floors
General Cleanroom Requirements
Here is a list of general require-
ments recommended as a mini-
mum for the successful operation
of a cleanroom. All cleanroom per-
sonnel should be aware and follow
these requirements at all times.
• All personal items such as keys,
watches, rings, matches, lighters
and cigarettes should be stored
in the personal locker outside the
gowning room.
• Valuable personal Items such
as wallets may be permitted in
the cleanroom provided they are
never removed from beneath the
cleanroom garments.
• No eating, smoking or gum
chewing is allowed inside the
cleanroom.
Figure 1
NEGATIVE PRESSURE CLEANROOM FOR
HANDLING POTENT COMPOUNDS
Cleanroom
Z = P1
• Only garments approved for
the cleanroom should be worn
when entering.
• No cosmetics shall be worn in
the cleanrooms. This includes:
rouge, lipstick, eye shadow,
eyebrow pencil, mascara, eye
liner, false eye lashes, fingernail
polish, hair spray, mousse, or
the heavy use of aerosols, after
shaves and perfumes.
• Only approved cleanroom
paper shall be allowed in the
cleanroom.
to touch any item or surface
that has not been thoroughly
cleaned.
tweezers should be used to
handle product.
used in the cleaning process
should be cleaned to the
same degree as the cleanroom
surfaces.
• No tool should be allowed to
rest on the surface of a bench
or table. It should be placed on
a cleanroom wiper.
• Only cleanroom approved
wipers are allowed to be used.
The wipers must be approved
for the class of cleanroom being
cleaned.
• All equipment, materials and
containers introduced into a
sterile facility must be subjected
to stringent sterilization prior to
entrance.
• No one who is physically ill,
especially with respiratory or
stomach disorders, may enter a
sterile room.
= Air Flow
Z = HEPA
Filtered Air
Definitions
HEPA Filter - High Efficiency
Particulate Air Filter
Viable - a particle capable of
living, developing, or germinating
under favorable conditions, i.e.,
bacteria.
Non-viable - typically dust or liquid
particles
Airborne - carried by or through the
air
Cleanrooms for Handling Potent
Compounds
For handling potent compounds,
i.e., toxic materials, in addition to
the requirements described for a
cleanroom, precautions need to
be taken to avoid spreading the
toxic material to adjacent areas.
This may be achieved by main-
taining a negative pressure dif-
ferential between the cleanroom
and adjacent area so any hazard-
ous powder or aerosol is contained
within the cleanroom, i.e., P3 ~
P2 > P1 (Figure 1). This is ac-
complished by designing the fa-
cility with HEPA filtered incoming
air and providing HEPA fil­tration
at the exhaust. Also providing a
higher flow through the exhaust
filters to assure proper flow, pres-
sure differential and sufficient
air changes in order to meet the
required room classification; this
setup does not allow air from the
cleanroom to enter into adjacent
areas. Additionally, by providing
localized exhaust or incorporat-
ing isolators onto manufacturing
equipment, the control of aerosols
and dust from handling powders
is increased. Note that personnel
enter the cleanroom through the
gown­ing area whereas equipment
and materials are brought through
the air lock.
References
1. ISO EN 14644-1, -2, -5, -9
International Standards Organiza-
tion Cleanroom Standards
2. FDA Guidance for Industry –
Sterile Drug Products produced by
Aseptic Processing – CGMP Sep-
tember 2004

Equipment and Supplies – all sup- Gowning Area Air Lock 3. EU GMP Annex 1- Manufac-
plies must meet the Class C or ISO Z = P2 Z=P3 ture of Sterile Medicinal Products
7 Area minimum requirements 4. ISPE – International Society
• Cleaning and disinfecting for Pharmaceutical Engineers
solutions
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